The mechanisms underlying mental stress ischemia (MSI) have not yet been elucidated, and it is not known which pafients are at increased risk of developing MSI. In particular, litfie is known about the psychological correlates of MSI. Depression, which is often linked to stress, affects about 20% of patients with CAD and is an important risk factor for death and subsequent cardiac events. Depression is associated with a failure to activate a neural circuit including the anterior cingulate, other areas of the medial prefrontal cortex and the hippocampus, which have inhibitory inputs to the amygdala. Failure of inhibition of the amygdala could result in peripheral activation of cardiovascular and neurohormonal responses through the hypothalamus-pituitaryadrenal (HPA) axis and the sympathetic nervous system (SNS). These pathways could increase the risk of MSI and contribute to endothelial damage and vascular resistance in CAD patients with depression. We propose a comprehensive approach to study the mechanisms by which, in CAD patients, the brain and neurohormonal pathways involved in depression lead to abnormal cardiovascular responses to mental stress, including MSI and peripheral vascular dysfuncfion. Our central hypothesis is that depression, and neurobiological pathways linked to depression, play an important role in mental stress-induced ischemia. We also hypothesize that these same neurobiological pathways are involved in peripheral vascular dysfunction during mental stress. The aims of this project are: 1) Assess the relationship between MSI and depression. 2) Using positron emission tomography (PET) and 0-15 water, assess brain correlates of MSI in CAD patients. 3) Using positron emission tomography (PET) and 0-15 water, assess brain correlates of peripheral vascular function during mental stress (vasoconstriction, arterial stiffness and reactive hyperemia). We hypothesize that depression is more common in patients who develop MSI than those who do not, and that brain areas involved in depression (anterior cingulate, hippocampus) that have inhibitory function on stress hormonal systems with pathways to the heart, will show decreased function during mental stress in patients who develop MSI and patients who develop peripheral vascular dysfunction during mental stress. For Aim 1, the relationship between MSI and depression will be assessed in all 650 participants in our PPG. For Aims 2 and 3, we will select 80 subjects with MSI and 80 subjects without MSI from the pool of 650 patients. Each subject will undergo PET scanning of the brain in conjunction with mental stress and a counting control using established methods.